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Friday, August 1, 2014

Yesterday's post on Treponemal diseases among humans (Treponema pallidum is a bacteria whose subspecies provoke yaws, bejel, pinta and venereal syphilis) suggested that the dates mentioned in
academic papers are underestimates. I disputed the dates because they are based on the assumption that humans entered America only 16.5 kya and also because the manifestations of Treponemal
disease in Homo erectus was rejected because the calculated mutation rates for the T. pallidum bacteria was considered too slow.

I believe a bit of proof for my position is required, and that is what today's post will look into.

The phylogenetic tree of Treponemal subspecies

In my previous post, I mentioned a paper (Harper et al., 2008) [1], which presented a phylogenetic tree rooted on a non primate species (rabbits, which are affected with venereal syphilis, caused by the
Treponema paraluiscuniculi strain). The tree included the human subspecies which cause yaws T. pallidum subsp. pertenue, endemic syphilis or bejel T. pallidum subspecies endemicum
and the agent of venereal syphilis, T. pallidum subsp. pallidum is the cause of venereal syphilis.

Additionally it showed a strain of T. pallidum that infected baboons (Papio cynocephalus) in Guinea.

The tree is shown below (from Harper et al., 2008) [1]:

The distance between the rabbit syphilis strains (T. paraluiscuniculi) and the human - baboon strains of T. pallidum (T.p.) is clear, but not so remarkable. What is striking is the very little
variation between all human subspecies and the very close proximity of the Baboon Strain from Guinea (1962) to the human pertenue subspecies.

Actually, the simian strain is so similar to the human ones that the paper [1] pointed out that it "could not be distinguished from subsp. pertenue strains using the polymorphic data in this study" [1].

The authors noticed this similarity and genetic closeness, and since the ancestors of Humans and baboons split some 25.7 to 62.5 Mya [2], which is quite a long period of time, they suggest an
"early emergence of these strains in human history" [1]. Early indeed, I would say very ancient, rooted in our distant ancestors (H. erectus? H. habilis?).

Another explanation for these very similar strains could be a shared disease that affects both humans and primates, in which there are recent cross-species infections between both parties.
This means that baboons may in fact be a reservoir of the disease in the wild or, alternatively that they became infected due to human contact. The authors [1] noted that the wild baboons are
infected with yaws in West Africa but could not establish any links to humans. [1]

This alternative was further investigated in another paper by Harper et al., 2012, [3]: During the four years that separated both studies, the Guinean baboon strain collected in 1962 was typed as
belonging to the Fribourg-Blanc strain which is "more closely related to T.p. subsp. pertenue laboratory strains than to subsp. pallidum or endemicum strains" [3], in other words
it is closer to the yaws vector than to the bejel and venereal syphilis strains. And this is exactly what the tree above shows.

More recently, Zobaníková M et al, (2013), [5] studied the genetic sequence of the T.p. Fribourg-Blanc strain and suggested renaming it as Treponema pallidum ssp. pertenue strain
Fribourg-Blanc. They also confirmed that it "clustered with other TPE strains (especially with the TPE CDC-2 strain)", that is, with the human yaws causing T.p. subsp. pertenue of
Western Africa and Indonesia. The Tree published in that paper (Fig 1. in [5]) portrays this proximity in a very clear manner.

Harper et al.'s new paper [3] also has a phylogenetic tree, basically the same as the one shown above, from their previouspaper, but now including two new baboon T. p. samples, from olive
baboons (Papio hamadryas anubis) taken at two separate sites in the African bush: [3]

The tree shows that the baboon strains from Serengeti National Park (SNP) and Guinea were thee first (oldest) to split from the tree leading to all human strains and to the
Lake Manyara National Park (LMNP) baboon strain. This LMNP strain falls within the yaws provoking subspecies in humans (T.p. subsp. pertenue). Below is a Wikipedia photograph of
an olive baboon:

So we have two wild varieties found in baboons from two separate locations very distant from each other (Guinea on the West coast of Africa and SNP in Tanzania, on the Eastern side of Africa) and
despite belonging to non-humans, they are genetically very close to humans.

But despite the similarity between the human T.p. pertenue strain and the baboon strains, the authors were unable to find which was "the closest relative to the baboon strains among the human subspecies". [3]

As the presence of yaws among baboons was noticed only recently, this fact suggests that it may be a new ailment caused by a novel T.p. subspecies among baboons, however the paper [3]
finds evidence to the contrary: these strains are indeed very old and the reasons are the following:

Humans and LMNP baboons share two synonymous substitutions which could only have arisen from a common ancient origin for the strains shared by both species. The probability of a convergent
evolution which replicated the same mutation in different strains affecting different species is virtualy zero. So they were inherited by baboons and humans from a common ancestor.

The national parks where the baboon strains were collected (SNP and LMNP) are not far from each other (only some 170 km - 105 mi.) yet, the tree shows that the strains are genetically
different: four mutations found in four different genes. This diversity implies that the LMNP strain split from the SNP strain a long time ago.

The paper concludes that: [3]

"If baboons are an important source of human infection, one might have expected human subsp. pertenue strains from West Africa to resemble the Fribourg-Blanc baboon strain
collected in Guinea rather than other human subsp. pertenue strains from distant locations such as Samoa and Indonesia. Instead, all human T. pallidum strains appear to share a common origin.
If further evidence demonstrates that the LMNP strain, like the other baboon strains, diverged prior to all human strains, and that the baboon strains form a paraphyletic group from which human strains are excluded, this will provide
further support for the hypothesis that the T. pallidum strains that infect baboons have inhabited their hosts for a long period of time, are genetically diverse, and are distinct from human strains.
Further, if T. pallidum strain phylogenies are congruent with host phylogenies, the evidence will indicate that this pathogen has evolved with its primate hosts, including humans, over millions of
years." [3]

The non-orthodox comments

Those conclusions are obvious: how could South East Asian and Melanesian human strains resemble African baboon strains unless they shared a common origin. And may I add, that at least is older than the
Out of Africa migration of mankind (orthodox science places this event some 70 kya) and maybe older if we accept a Homo erectus migration as the carrier of T.p. out of Africa around 1.6 Mya.

So it is now evident that baboons and humans share a similar strain of this bacteria. It has been with baboons for millions of years (we split form baboons over 25 Mya)[2] and it has mutated very
little over this long span of time. The human strains should, by analogy be very ancient too, and looking at the trees depicted above, the distance between human and baboon strains is very small:
the branches are all very short. The only exception, the only one with relatively "longer" branches is the venereal syphilis agent, T.p. subspecies palidum (in blue in both trees).
This is of course the most recent mutation, which took place in America.

The fact that it is "recent" and appeared in America among humans immediately boxes it into the mental mindset of orthodox scientists as being not older than 15-20 ky. So they will focus their
studies and seek support in data that validates this date (being biologists and not anthropologists, they assume the date is correct, so they use it in their calculations).

But in my mental framework, recent means that it is younger than the other subspecies, which may be 1.5 My old, so then this strain is younger than one and half million years old. Just how young
depends on the calculations and the assumptions used.

The T.p. bacteria mutates very slowly. This is evident by the lack of diversity found between all strains even though millions of years have elapsed.

The slower the mutation rate the older the most recent common ancestor will be, yet the paper by de Melo et al., [4] dismissed the possible appearance
of tremponematosis among H. erectus because they calculated a mean mutation rate of 6.35×10-10 substitutions⁄site⁄year. Which was, according to them, far too slow
compared to other bacteria: E. coli: 4.5–5.0×10-9, Buchnera 8.2×10-9 subs⁄site⁄year).

It is worthwhile pointing out that the mutation rates in bacteria are variable, see for instance Helicobacter pylori with rates between 6.2×10-7 and 9.2×10-7 [4] which
compared to E. coli and Buchnera give a difference of more than two orders of magnitude: 75 to 200 times!

As expected, de Melo et al.'s paper settled for the option which gave them a mutation rate for T.p., which is intermediate between both extremes (of 4.09x10-8 subs⁄site⁄year).
A Salomonic decision which fitted neatly with their calculations for an American origin for T.p. subsp. pallidum between 16.5 and 5 kya.

But this time frame differs with the conclusions of Harper et al.: "...this pathogen has evolved with its primate hosts, including humans, over millions of years." [3]

I decided to check their calculations, and the values I obtained are shown below:

De Melo et al., use the expression TMRCA = K ⁄ 2 x Rate. In their paper they indicate that K= 2,96 x 10-4 subs⁄base pair. Which arises from
dividing the 327 substitutions detected by the 1.1 Million base pairs found in T. pallidum.

The "Rate" is the "substitution rate" or mutation rate of the bacteria being studied.

I used the "rates" that they obtained in their paper for each of the hypothesis that they tested; I also used their average mutation rate for T. pallidum, and for each of them I used the above
formula to calculated the TMRCA. I was quite surprised to see that my values differed from those calculated in the paper[4] by between 3 and 20 times! I mentioned yesterday that I could not
understand their calculations (I am an engineer by the way so I am very used to cracking numbers and equations), and today I ratify my comment. I am baffled.

The TMRCA calculated using their expression are far to "young" and in fact are smaller than the ages calculated by de Melo et al.

Closing comment

In my opinion the reason for this discrepancy and the recent age obtained for TMRCA using the expression above is due to the "Rate" used in the formula.

The value for the mutation rate for T. pallidum is much lower than estimated by de Melo [4]. Using a smaller "rate" in the expression above will give a higher -older- value for TMRCA.
And, as Harper et al., proved [1], T.p.'s mutation rate is indeed extremely low, and that is why there is so little difference between the baboon strain and human strains after such a long period
of time since the divergence of both our species.

The fact that other bacteria mutate quicker is irrelevant, each microbe adapts to its host and if doing so implies less mutations, it should be recognized and accepted.

The closing comment is therefore: the human versions of T. pallidum are much older than the dates proposed by de Melo et al., [4], the youngest of all subspecies, the venereal disease agent,
T.p. subsp. pallidum very likely originated in America as thjey suggest, but did so long ago, well before the 16.5 ky indicated by them [4]. The H. erectus origin of our T.p. subspecies can not be
dismissed in this context:

The similar geographic ranges of the oldest subspecies of T.p., (yaws causing agent pertenue) in Southeast Asia and Africa matches that of Homo erectus in Asia and its homeland in Africa.
This may not be a coincidence, but a casual relationship: T.p. reached Asia inside its host, H. erectus.

The other mutations of T.p. (such as bejel) match the regions occupied by Eastern Neanderthal and Denisovans... could there be a relationship between them and the bacterial strain?

Yesterday's paper showed that there were two possible mutational routes from the African yaws strain or the Eurasian bejel strain to the Amerindian yaws (and venereal syphilis) strains.
The yet non-sequenced pinta strain in America may hold the key to understanding which of those routes is the most probable one:

If it is the African yaws strain, maybe it shows the Modern Human emergence and migration OoA carrying the variant that eventually reached America.

If it is the Eurasian Neanderthal strain, then it was them who reached the New World, originating pinta there and later Amerindian yaws.

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